A key obstacle to successful treatment of drug addiction is relapse, which is frequently precipitated by exposure to stress. Relapse has been modeled in animal studies through reinstatement of responses to drug self-administration or conditioned place preference (CPP) by drug, cue or stress. We and others, have demonstrated that a variety of drugs of abuse, such as morphine, cocaine and more recently nicotine, can activate the transcription factor CREB (cAMP response element binding protein) and this activation is necessary for subsequent behavioral responses to these drugs. More recently, we have shown that CREB is required for stress-induced reinstatement of cocaine conditioned place preference (CPP), but not drug- induced reinstatement. The mouse is a tractable animal model that allows for investigation of relapse at the levels of behavior, neural circuitry and molecular mechanisms. In this proposal we will utilize mice homozygous for a targeted mutation in CREB (CREB alpha/delta mutant mice) to test the hypothesis that CREB is a central signaling molecule required for stress induced reinstatement of drug seeking behavior. We will test this central hypothesis in three specific aims. In Aim 1, we will investigate if activation of the transcription factor CREB is critical for the manifestation of reinstatement behavior following various stressors using a conditioned place preference paradigm (CPP), and determine the role of corticosterone and CRF in this response. As both stress and cocaine reinstate CPP in wild type mice, these circuits must converge on a final common pathway. In Aim 2, we will identify the pathways specific for stress versus drug induced reinstatement, as well as points of convergence. Moreover, retrograde tracing studies will enable us to identify the precise location of these neurons in key brain areas in the reinstatement circuitry. Lastly, in Aim 3 we will determine which genes in these key brain areas are direct CREB target genes. These studies will allow us to address the molecular mechanisms underlying drug relapse. This information will be valuable for the development of pharmacotherapeutic approaches that focus on regulation of CREB and its target genes. These studies may give rise to novel potential therapeutics that can ultimately be translated to the clinic for relapse prevention in humans [unreadable] [unreadable]